“The price we pay for our amazingbehavioral complexity and flexibility isthat we’re also susceptible to deleteriousmutations that can cause mental disorders.”

SETH GRANT

Edinburgh University

explain how vertebrates expanded their sets of genes: Over
the millennia following the duplications, the extra gene copies
accumulated smaller mutations, which in turn diversified their
DNA sequences and function. The events gave vertebrates a
much larger molecular toolbox to perform biological functions.

These insights led the British scientists to wonder if these
genomic evolutionary events were responsible for generating
vertebrates’ more sophisticated behavioral repertoire — the
first time anyone has examined the effects of these events on
learning, memory, cognitive flexibility and attention.

In the first part of the study, the researchers genetically
engineered mice to remove each of the four diversified vertebrate
Dlg genes. They had them do tasks on an iPad-like touch
screen that involved, for example, learning to associate objects
with locations, and detecting and responding to targets briefly
displayed on the screen, which they did by nose-poking stimuli
on the screen to obtain rewards. Compared with normal mice,
the mice lacking the Dlg4 gene had a very difficult time doing
more advanced tasks; those lacking the Dlg2 gene performed
worse on many tests; and those lacking the Dlg3 gene actually
performed better on some tasks, the team found.

The results prove for the first time that the evolution
of the four Dlg genes “produced distinct and sometimes
complementary functions,” says genetic researcher Seth Grant,
MD, of Edinburgh University, who led the studies.

“In turn, that evolution had the overall effect of increasing
the complexity in the way vertebrates regulate their behavior,”
he says.

In the second part of the study, the team set out to test
whether the function of the Dlg genes was the same in mice and
humans — an important question given that scientists routinely
apply findings on mice and other rodents to humans.

First, the team compared the DNA sequences and RNA
expression maps of the brain in mice and humans, and found a
high degree of similarity in Dlg genes between the two species.

But they also wanted to test that similarity on a functional level
since human brains are much larger than mouse brains, and
therefore the genes controlling their behavior might manifest
very differently.

The researchers gave touch-screen tasks testing the same
cognitive functions to both mice and people with known
mutations in the Dlg2 gene. The human participants — three
of whom had been diagnosed with schizophrenia, one who had
not — had difficulty in the same domains of cognition as the
impaired Dlg2 mice, including visual discrimination and cognitive
flexibility, visuo-spatial learning and memory, and attention.

The findings demonstrate that the role of Dlg2 in regulating
specific cognitive functions has been “conserved,” or remained
essentially the same since it first arose. The results also show
how mutations in those genes might lead to mental illness. As
such, the research provides an important evolutionary insight
into the way the fundamental molecular mechanisms of human
cognitive complexity and mental illness arose deep in our
ancestry, says Grant.

“The price we pay for our amazing behavioral complexity
and flexibility is that we’re also susceptible to deleterious
mutations that can cause mental disorders,” he says.

The findings may also pave the way for practical
applications, by identifying some of the genes and proteins
involved in higher cognitive functioning as well as in mental
illness, adds study co-author Tim Bussey, PhD, of the University
of Cambridge. The study also shows how humans and rodents
can be tested on highly comparable cognitive tasks, thereby
highlighting the possibility of improved cognitive translation
between preclinical and clinical research, says Bussey, who
developed the touch-screen technology.

“I think this more accurate translation can only help with
drug discovery and other medical advances,” he says. n